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Wednesday, October 17, 2012

Arrowhead Research Breaks Up Dynamic PolyConjugates into Two

Arrowhead Research announced yesterday that it had received Notice of
Allowance from the USPTO for a Dynamic PolyConjugate-related patent application
(for systemic RNAi delivery). Instead of
it being your run-of-the-mill patent PR involving known technology that finally received patent protection, it was really about revealing Arrowhead’s
fundamentally new approach towards DPC delivery (for my take on the original form of DPC, see here).

The patent, part of a series of patent filings that have come out recently, shows that under Roche’s ownership, the technology
has morphed through a number of iterations from the original complex
polyconjugate chemistry combining endosomolytic polymer, masking groups, RNAi
trigger, PEG, and cell targeting ligand all in one molecule (schematic shows such molecule and presumed mechanism of delivery), into
one where a RNAi trigger and the masked polymer, both targeted individually, are
administered as separate agents.

One problem with the original design has been that combining all
the functional groups, including negatively charged RNAi triggers and
positively charged polymers, into one molecule was not particularly easy. The tendency to aggregate and poor yields
made it a quite expensive and difficult-to-scale proposition.

Turns out that such complicated chemistry wasn’t needed
after all. As long as the RNAi trigger
and the masked endosomolytic agent end up in the same place, it does not make
much of a difference whether they are getting there as one molecule or
separately. In the example provided, namely for gene knockdown in hepatocytes, the RNAi trigger could be conjugated to
either cholesterol or a cluster of galactose sugars, whereas the masked
endosomolytic polymer was targeted to the hepatocytes by galactose. Viewed differently, the polymer allowed the
cholesterol-siRNA that apparently gets trapped in the endosomes when alone to be released
into the cytoplasm. Hence, the
multi-fold increase in potency (Arrowhead Research says it’s 500-fold) over
Alnylam’s original 50mg/kg cholesterol-siRNA report (Soutschek et al., 2004).

Another potential advantage of this separated approach is
that it makes each component smaller, perhaps 'one day' enabling subQ
dosing. However, as mipomersen's FDA AdCom meeting briefing docs show, when it comes to subQ dosing, be
careful what you wish for.

Manufacturing appears to have been one of the issues
delaying the clinical translation of DPCs for quite some time (Arrowhead Research says they are ready to file an IND in Q2 2012 for Arc520 in HepB). Toxicity, mainly due to
premature unmasking in the blood instead of in the target cell endosome, seems to have been the other main reason. Such premature unmasking also adversely affected circulation times, thereby rendering attempts to get beyond the liver, one of the original promises of DPCs, futile. We will probably get word from the company
soon what solutions it found for this challenge, but it seems that, based on the emerging patent literature (including
non-human primate data; e.g. WO 2012/083185), masking the membrane penetrating peptide
mellitin with endosomal protease-sensitive groups, is a promising approach.

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